Maturation of dendritic cells determines whether an antigenwill elicit a tolerogenic or immunogenic response. Endogenous pathways are required to maintain peripheral tolerance to self-antigens by deleting, anergizing or expanding T regulatory cells. Work during the past funding period of this program project revealed that IgG immune complexes can promotestrongly immunogenic responses if the normalinhibitory constraint is overcome. We will test the hypothesisthat IgG immune complexes, in the steadystate, maintain tolerance through distinct DC subsets by preferentially eliciting inhibitory receptor signaling. This endogenous pathwayhas been shown to be perturbed in autoimmune susceptible mouse strains and human population. This hypothesiswill be tested by 1) Determining the contribution of the inhibitory FcR expressed on DCsubsets to the autoimmune phenotype;2) Blocking activation or inhibitory FcR signaling on DCs in novel FcR humanized mouse models to determine their contribution to develop or maintenance of autoimmunity and 3) Dissecting the FcR signaling pathway on DCs that either promotes immunity or tolerance and its potential synergy with TLR signaling pathways. These studies will depend on the reagents and observations developed in the two other projects in this program project. The results of the studies in this projectwill, in turn, impact on the experimental approachesof the other projects. This synergy will allow us to developapproachesto restore tolerance in autoimmunity through the targeting and manipulationof maturationpathways in vivo.